Excitement took wing in the scientific community in the early 1990s, when the first gene therapy trial showed significant success, only to crash at the end of the decade with a patient’s tragic death.

Twenty years later, the excitement is back and greater than before. Although safety remains a concern, investigators are breaking ground in cell and gene therapy, and many believe that ultimately, a string of cured cancers will follow.

“We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer,” said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapy’s pioneers. “It still may happen here and there, but it’ll be kind of like people dying of pneumonia. It’s like, ‘He died of pneumonia? That’s kind of weird.’ I think cancer can be the same way.”

The excitement returned in spades in 2017 when the FDA signed off on a cell-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for the treatment of B cell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a person’s own T cells to attack tumor cells.

“We’re entering a new frontier,” said Scott Gottlieb, MD, then-FDA Commissioner, in announcing the groundbreaking approval.

Gottlieb wasn’t exaggerating. The growth in CAR T-cell treatments is exploding. Although only a handful of cell and gene therapies are on the market, the FDA has projected that it will receive more than 200 investigational new drug applications per year for cell and gene therapies over the next few years, and by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.

“Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell,” Hwu said. “The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but don’t recognize the normal cells.” Receptors recognizing and then attacking normal cells is what can cause toxicity.

In neurology, a number of neuromuscular diseases, most prominently spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), have already begun to assess gene therapies (

). In SMA, Novartis Gene Therapies's intrathecal (IT) onsemnogene abeparvovec (Zolgensma) is already approved for use. In October 2020, more data were announced from the phase 3 STR1VE-EU trial of the therapy, suggesting it offered significant benefit in patients with SMA type 1. Of the 32 patients in the study, 31 had survived event-free by the data cutoff point. Additionally, 21 (65.6%) achieved motor milestones not seen in the natural history of the disease, including 6 patients (18.8%) who sat independently for ≥10 seconds.

Also in SMA, Biogen recently dosed the first patient in a phase 4 trial of nusinersen (Spinraza) in patients who have unmet needs despite treatment with onsemnogene abeparvovec, with plans to evaluate 60 patients aged up to 3 years. The primary study group is expected to include 40 infants aged 9 months or younger (at the time of first nusinersen dose) who have 2 copies of SMN2 and received nusinersen at 6 months and older. A second study group will include 20 children within a broader age range (up to 3 years).

In DMD, microdystrophin gene transfer using recombinant adeno-associated virus serotype rh74 (rAAVrh74) driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7) is being evaluated as effective therapy. As well, Sarepta Therapeutics recently announced the first clinical data for SRP-5051, which demonstrated proof-of-concept in the phase 2 MOMENTUM study (NCT04004065) in DMD. The results supporting continued dose escalation, and the therapy was found to be generally well-tolerated across all doses administered. Likewise, a number of gene-based treatments are being assessed and showing promise in diseases such as SCN1A-positive epilepsy, Parkinson disease, and Alzheimer disease, among others.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvania’s gene therapy program, is cautious about the FDA’s predictions, saying she’d be “thrilled” with 5 cell and/or gene therapy approvals annually.

“For monogenic diseases, there are only a certain number of mutations, and then we’ll plateau until we reach a stage where we can go after more common diseases,” Hordeaux said.

“Safety has been the main brake around adeno-associated virus vector (AAV) gene therapy,” added Hordeaux, whose hospital’s program has the institutional memory of both Jesse Gelsinger’s tragic death during a 1999 gene therapy trial as well as breakthroughs by Carl June, MD, and others in CAR T-cell therapy. “Sometimes there are unexpected toxicity [events] in trials.…I think figuring out ways to make gene therapy safer is going to be the next goal for the field before we can even envision many more drugs approved.”

Natural killer (NK) cells are the research focus of Dean Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Children’s Hospital. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA investigational new drug application. He is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His efforts are geared toward pediatric sarcomas.

“The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells,” said Lee, who is also director of the Cellular Therapy and Cancer Immunology Program at Nationwide Children’s Hospital, at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital, and at the Richard J. Solove Research Institute.

However, Lee said, NKs have wider potential. “This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space],” he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis’ proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. Lee said the pivot toward treating COVID-19 with cell therapy was because “some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.”

The revolutionary gene-editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020. For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones. National Public Radio did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.

Ten patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the 

 Two different groups, one based in Nashville, Tennessee, and another based at Dana-Farber Cancer Institute in Boston, Massachusetts, have reported on this technology.

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Children’s Research Hospital, said, “There’s a lot of activity to really explore these therapies with diseases that are much more common than cancer.”

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence, such as conditions associated with inflammatory clots, are also being studied.

Hordeaux said she foresees AAV being used more widely to transmit neurons to attack neurodegenerative diseases.

“The neurons are easily transduced by AAV naturally,” she said. “AAV naturally goes into neurons very efficiently, and neurons are long-lived. Once we inject genetic matter, it’s good for life, because you don’t renew neurons.”

The process of working out all kinks in manufacturing also remains a challenge. Rapid production is difficult, too, because of the necessary customization of doses and the need to ensure a safe and effective transfer of cells from the patient to the manufacturing center and back into the patient.

Other factors that slow down launches include insurance coverage, site certification, staff training, reimbursement, and patient identification. The question of how to reimburse has not been definitively answered; at this point, insurers are being asked to issue 6- or even 7-figure payments for treatments and therapies that may not work.

“CAR T, I think, will become part of the standard of care,” Gottschalk said. “The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off-the-shelf products to get around some of the manufacturing bottlenecks. I believe those issues will be solved in the long run.”

Articles

Features

Advancements in gene therapy approaches have opened the door for a glimpse into the future of care for a number of diseases.

Tapping Into the Potential of Cell and Gene Therapy

Results of the TEMPO trials, a combination of three phase 3 studies and an open-label extension, will be used to examine the effects of tavapadon, a Parkinson disease (PD) drug designed by Cerevel Therapeutics, in patients with early-onset PD and those with late-stage PD.

Approximately 1200 individuals, aged 40 to 80 years, will be enrolled in the 3 trials; the first patients were dosed in November 2020. TEMPO-1 (NCT04201093) and TEMPO-2 (NCT04223193) will include patients with early-onset PD and, to determine tavapadon’s efficacy, will use change from baseline in the Unified Parkinson’s Disease Rating Scale (UPDRS) part 2 and part 3 combined score (

Patients included in TEMPO-1 and TEMPO-2 may not be on levodopa but can be on a monoamine oxidase type B inhibitor, such as rasagiline, and still qualify for the trials. TEMPO-1 will be a fixed-dose trial, while TEMPO-2 and TEMPO-3 will feature flexible dosing.

The TEMPO-3 (NCT04542499) trial will differ from the other 2 in that it will assess patients with late-stage PD, a population whose disease is severe enough to require the introduction of levodopa. The primary end point of TEMPO-3 is the change from baseline in “ON” time without troublesome dyskinesia.

All 3 trials are supported by a 58-week open-label trial that will continue to gather information on safety that will be needed for an eventual FDA submission.

Raymond Sanchez, MD, chief medical officer of Cerevel Therapeutics, told 

®, “We are trying to understand the benefits that tavapadon may bring to PD patients as both a stand-alone treatment in early stages of PD and as a potential adjunctive treatment to levodopa in more advanced stages of the disease.”

Tavapadon was designed as an orally bioavailable, once-daily partial agonist that selectively targets dopamine D1 and D5 receptor subtypes. The agent differentially activates the direct motor pathway, potentially driving motor benefit while minimizing the adverse effects (AEs) typical of drugs that nonselectively stimulate dopamine.

Across phase 1b and phase 2 trials conducted to date, tavapadon has demonstrated this motor control benefit with an improved tolerability profile relative to that of D2/D3-preferring agents.

Positive results from the phase 2 assessment showed that tavapadon met its primary end points by showing a statistically significant improvement in motor symptoms after 15 weeks. Researchers found a change of –9.0 points in UPDRS Part 3 scores for those treated with tavapadon, compared with –4.3 for those administered placebo (least-squares mean, –4.8; 

= .0407). Additionally, treatment compliance was high in both groups, and 82% of patients who received tavapadon completed the trial.

The randomized, flexible-dose study included 57 patients aged 45 to 80 years with PD and varying disease severity (their Hoehn and Yahr stage ranged from 1 to 3). The study included a 9-week dose optimization period followed by a 6-week period of stable dosing. In the phase 1 study, tavapadon doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg, and included an open-label multiple ascending dose study, which gave once-daily doses with up-titration to 5 mg, 15 mg, and 25 mg.

After 15 weeks, 50% of those treated with the study agent reported Patient Global Impression of Change statuses of either much improved or very much improved. In comparison, 25% of patients in the placebo group reported this status. There were no effects of significance on Epworth Sleepiness Scale score in either the placebo or tavapadon groups.

Tavapadon also showed a favorable tolerability and safety profile. Most of the AEs were deemed mild or moderate; the most common were nausea, headache, somnolence, and tremor.

Sanchez hopes that “even when [tavapadon] is introduced as an adjunct treatment to levodopa, given its long half-life and partial agonist mechanism of action, it can sustain motor control, allow practitioners to reduce the levodopa dose, reduce the dyskinesia burden, and still [give patients] the needed motor control.”

The data readouts for these trials will emerge collectively by the end of 2023. Sanchez noted that if the trials are successful, Cerevel Therapeutics plans to submit a new drug application to the FDA shortly thereafter. It will include all 3 TEMPO trials and the open-label extension.

REFERENCES
1. Cerevel Therapeutics announces first patients dosed in all phase 3 trials of tavapadon for the treatment of Parkinson’s disease. News release. Cerevel Therapeutics; October 30, 2020. Accessed January 7, 2021. 

https://www.globenewswire.com/news-release/2020/10/30/2117657/0/en/Cerevel-Therapeutics-Announces-First-Patients-Dosed-in-all-Phase-3-Trials-of-Tavapadon-for-the-Treatment-of-Parkinson-s-Disease.html


2. About the mechanism of tavapadon. Cerevel Therapeutics. Accessed January 7, 2021. 

https://www.cerevel.com/compounds/tavapadon/


3. Cerevel Therapeutics announces positive results from a phase 2 study of tavapadon in patients with early-stage Parkinson’s disease. News release. Cerevel Therapeutics; September 23, 2019. Accessed January 7, 2021. https://www.businesswire.com/news/home/20190923005097/en/Cerevel-Therapeutics-Announces-Positive-Results-Phase-2
4. Sohur US, Gray DL, Duvvuri S, Zhang Y, Thayer K, Feng G. Phase 1 Parkinson’s disease studies show the dopamine D1/D5 agonist PF-06649751 is safe and well tolerated. Neurol Ther. 2018;7(2):307-319. doi:10.1007/s40120-018-0114-z

Clinical Trial in Progress

Tavapadon’s rare combination of efficacy and minimal adverse effects may indicate
a step forward in the treatment of Parkinson disease.

Parkinson Disease Treatment Tavapadon Aims to Benefit From Unique Multitrial Designs

The global pandemic brought with it an enormous challenge for health care workers. But for the Alzheimer disease (AD) community, the past several months also brought the ongoing conversations around aducanumab, Biogen’s investigational amyloid-targeting agent, to the forefront. After its 2 phase 3 trials were cut short and a complex analysis suggested the therapy may offer benefit to patients, the therapy is awaiting an approval decision from the FDA—potentially a landmark moment for AD—a decision the agency recently delayed 3 months out to June 2021.

While the discussion about aducanumab’s potential has dominated conversations in the space of late, determining if this agent offers benefit is far from the community’s only challenge. To find out more about what a possible approval might mean for AD and for the physicians treating it, as well as what impact it may have on some of those obstacles, 

® spoke with the principal investigator in the aducanumab trials, Stephen Salloway, MD, MS, director of neurology and of the Memory and Aging Program, Butler Hospital, Providence, Rhode Island.

Q: What impact do you believe an approval of aducanumab would have for AD?

My take is that it would open a new modern treatment era for AD. It would just be the beginning—a stepping stone, rather than the final breakthrough. There was a really good quote the other day, from a colleague of mine, who said, “In order to get the best-in-class drug, we must have the first-in-class drug.” That’s how I see this.

It’s akin to azidothymidine (AZT) for HIV. There was no treatment for HIV, and when AZT was approved, it had limited use, but it stimulated the community to really get going with developing better treatments, and now they have developed really potent treatments that affect the disease course for HIV. I’m hoping the same thing would happen for us, and AD. No drug has been approved for 17 years for AD. The need is much greater now than it was back then, and this would be the first indication for mild cognitive impairment. There is no current indication for the earlier stage of the disease. And it’d be the first drug that actually targets the core pathology of the disease. There are a lot of great things on that side.

But where I see it as really being beneficial and moving the field is that it would then require us to use modern tools. We’d have to screen for amyloid status. Right now, we’d be using amyloid PET and cerebrospinal fluid, but soon we’ll have blood tests to do the same thing. That will get us on the move to figure out how to use those. We’ll have to screen for appropriate eligibility, making sure people meet the disease stage, making sure their MRI is doesn’t show extensive cerebral amyloid angiopathy. We’d have to learn how to monitor for and manage amyloid-related imaging abnormalities, which is a common adverse effect of AD therapies. On all those fronts, it would be a major advance in moving us forward.

If aducanumab became the standard of care, we’d have to [work on] add-on studies for people with early AD who had access to aducanumab. I imagine most [people] would want to go on aducanumab, rather than go into a clinical trial and [possibly] be on placebo. We’d have to show added benefit of a new treatment— or really, a combination treatment—with aducanumab plus something else, or aducanumab compared with something else.

Q: Do you think that that would happen relatively quickly if aducanumab is ultimately approved?

Well, I think it’ll be determined based on the uptake. If there is full FDA approval for the indication that we used to test the drug— which I would recommend that it be—that would be the label, and [then there would be widespread] reimbursement. Then I think there would be pretty broad uptake. Patients would have access to it, there’ll be a high demand for it, and then there will be pretty brisk uptake. We’ll figure out how to administer it to a larger number of people. That’s going to be a challenge, but I think we can overcome that. Once that happens, then that that basically establishes it as the standard of care.

Then you have an ethical problem, or [at least] a recruitment problem—you can debate whether it’s an ethical problem. If someone has access to a drug with some positive chance of benefit vs nothing, they’re going to choose [the drug], especially for a serious disease like AD. It’s a big commitment to be in these studies. You don’t want to dedicate yourself to something and turn down a treatment that might be of benefit to you. I think that will happen over the course of a year. It’ll take time to retool our trials to factor in aducanumab. Then, there is the whole issue of coverage—who pays for that? If we’re testing, let’s say, a tau drug plus aducanumab, and everyone is guaranteed to get aducanumab—some will get tau and some will get placebo—who pays for the aducanumab? Is it the sponsor of the tau trial? Is it Medicare? A combination? I don’t know. That’s another factor.

What’s likely to happen, or could, is approval of aducanumab in the United States, but no approval for a while outside the United States. Then, the trials of monotherapy, without aducanumab, would be conducted in other countries, which is good and bad. The rigor of US trials is pretty reliable, and I get [more] nervous the less developed the country is. [For instance,] we had a positive drug, Dimebon, many years ago, when it was tested in Russia, with a really great result. Then, when we tested it outside of Russia, we saw no benefit. We couldn’t replicate the findings. So, it just makes me nervous if we rely [on other medical systems], especially less developed medical systems, to prove the benefit of the drug.

Q: Do you think that the scales that are currently being used are adequate?

We always want the most sensitive and reliable measures we can develop, for sure. That’s especially challenging when we go earlier in the disease. Let’s say someone is showing pathological changes of AD with amyloid or tau buildup and no symptoms. Detecting change on a cognitive scale, in that case, is very challenging. The more impaired the patient, the easier it is to detect the change. And patients change more during the trials. That’s a very important factor: the rate of change. If you get a lot of people in a trial who are stable, then it’s very hard to show a drug’s benefit. You need at least a substantial group of people who are progressing in a detectable way during the trial.

We’ve made a lot of advances that I’m really excited about. One is that we can visualize the amyloid plaques safely now, and [do so] early on in the disease process. We can see the tau tangles, as well, with a brain scan. The blood tests and the plasma test [to detect plaques] look really good and they are coming on quickly—much more quickly than almost all of us expected. [Those tests will] be a real game-changer. Once we have a plasma test that’s reliable for detecting the disease state, and also helping to measure progression of change, that will be really helpful. [We’ll be able to] define a population that is amyloid positive, and we can target whatever stage of the disease—either preclinical, or early AD, or later AD— and verify that they have AD pathology. That’s really good.

Now we have drugs [in development] like aducanumab and others—it’s not alone—that actually target the plaques and can lower them demonstrably. That’s a big advance; don’t take that for granted. The FDA’s question is whether we can show a correlation between the lowering of the amyloid plaques and a clinical benefit, and that’s where there’s a debate. Aducanumab has had mixed results, but [there are some explanations]. First of all, the trials got interrupted. That made data interpretation more challenging. And then there was a dose adjustment for a large segment of the population—the 

carriers—midway through. Dose is important for these drugs, and a lot of [the trial participants] didn’t get to the highest dose and have full exposure to that, which makes interpretation difficult. One study clearly showed a benefit, and one study didn’t. I think it’s open to interpretation.

Q: How would you describe the impact of the technological and diagnostic advances you alluded to earlier?

We have made major, major advances on the diagnostic side and biomarker side. I would consider the blood biomarker to be a major, game-changing breakthrough. Once that comes into clinic—it’s already coming into research—and we start using it for research, to screen, that will be the first major test for this. If we can reliably use that to screen, especially for the preclinical population—so we don’t have to do a PET scan on everybody to figure out who’s likely to be positive—that will be huge. At least initially, we’ll use PET scans to verify [status]. But if [the biomarker is] good enough, you won’t even need the PET scan unless you want to measure the change in amyloid-PET. That would be our first clinical use, in a research setting. If that’s good and reliable, then it’ll go into clinical practice, and then we’re in a whole new world. Then, any doctor who treats older patients will need to become familiar with it because they’ll need to know how to use it. That will be driven by therapy, if we have one. A doctor is going to be motivated if there’s something they can do. If there’s nothing you can do about, [say], prostate cancer, there’s much less motivation to screen. But now there are a lot of treatments for prostate cancer, colon cancer, breast cancer—all of the other cancers that have routine [screening] now. It will be the same thing for AD. That’s why it’s important to have at least 1 drug approved, because that will motivate the clinical community to get more engaged.

Clinical Viewpoint

The director of Neurology and the Memory and Aging Program at Butler Hospital and principal investigator in the aducanumab clinical trial program discussed the investigational agent and the current landscape of care.

Aducanumab and the Alzheimer Disease Treatment Landscape

Migraine care has benefited in recent years from the introduction of novel therapeutics aimed at preventing attacks by targeting calcitonin gene-related peptide (CGRP) and the corresponding receptors. Acute management, too, has benefited from these developments.

, associate professor of neurology, Michigan Medicine, and 

, assistant professor of neurology, Mayo Clinic Scottsdale, offered their perspectives on how this has impacted the care of their patients, such as how the shift in expectations outcomes has impacted treatment selection, and shared some of their best practices in migraine treatment. Additionally, they spoke to the intricacies of measuring pain relief and monitoring the onset of action of therapy, and the vital nature of doctor–patient communication when optimizing the efficacy of treatment.

According to Cooper, the best question the treating physician can ask is about the control of a patient’s migraine. He noted that the responses of treated patients may vary, but they often will note that their headache is reduced or that they’re feeling better, but that they haven’t quite achieved their desired outcome.

“One of the things I like to ask, if I’m assessing someone for their headache [therapy] effectiveness, is, ‘How many times in the last month have you been disabled or incapacitated from an acute migraine?’” Cooper said. “Meaning, how many times did they have to stop their plans [relating to] work, family, or social events? Incapacity—taking people out of their daily lives—is a huge issue for people with migraine.”

Probing about the onset of action for a given medication can be tricky, Cooper added. The inquiry itself relies on the assumption that patients are taking medicines at the onset of symptoms. With triptans, for example, the literature is most supportive of efficacy when they’re administered as close as possible to the beginning of an acute headache, Cooper noted. The same appears to be true for the newer medications, as well. A further complicating factor, Cooper explained, is that patients’ response times vary—from as short as 10 to 15 minutes to as long as 4 to 6 hours, or even a full day.

“We know that triptans and some of the gepant-class medicines work on the lining of the brain, where the meningeal pain through the trigeminal fibers is sent deep into the brain itself,” Cooper said. “If you wait too long, and that signal from the lining of the brain becomes amplified and it gets reactivated back into the brain stem itself, you’ve lost your opportunity for medications that work in the periphery to have [efficacy].”

Importantly, many patients need to ration their acute treatments because usage should be limited to 2 to 3 days per week. A patient with 15 headache days per month may hold off on administering medication, to save it for the days and times when they most cannot afford to be incapacitated. In some circumstances, Cooper explained, patients tend to wait because of the prodrome period. This can cause some confusion and awareness impairment for patients, which can delay the time they take to recognize that they are headed for an attack.

Delays in treatment can also be due to fear of adverse effects or to a perceived lack of efficacy. The consequences of such delays are, mainly, more severity and longer duration of migraine, as well as incomplete response to therapy.

“Our patients with migraine [often] come to us with a history of stigma: a history of family members, the lay public, [people at] their workplace, and even their medical and health care providers not listening to them and not communicating with them. That’s why it’s so important that once they come to us, as their neurologists and their headache treatment providers, that we emphasize how dedicated we are to communicating with them,” Starling explained.

Communication is essentially the key to the entire patient-doctor relationship, Starling emphasized, beginning with the first appointment and extending through follow-up and every subsequent visit.

Part of establishing a strong relationship includes properly describing the treatment plan with the patient. This includes giving them a plan for when medication does not achieve the required efficacy; being sure they know when to contact the physician or to potentially head to the emergency department; and outlining what to expect in all of these situations.

“You want to make sure that the patient has a plan [for different scenarios,] because those events can be really scary, and often they’re not in a position where they can appropriately advocate for themselves,” Starling said. They should also have a follow-up plan, detailing when to update their doctor and how soon they should anticipate another visit to the office. Additionally, providing the patient with the information the physician will require for the visit can help with the efficiency and accuracy of both the visit and communication.

Starling said that going over all these specific factors helps optimize the treatment plan, and also reinforces the importance of monitoring pain relief and therapeutic effect onset. She also noted that when the patient keeps a reliable headache diary, it not only helps patient-doctor communication but provides valuable information about attack patterns, such as clustered attacks or unbroken attacks, which require distinct therapy approaches.

“A reason that many patients find keeping a headache diary to be frustrating is that their doctor doesn’t ask to look at it,” Starling said. “If you ask for it and [actually] look at it, they’re more motivated to keep it.” And it’s not necessarily difficult to keep a diary, she added: “They can keep it on their phone, using any type of app. A lot of my patients like using the app Migraine Buddy. Or, they can use an old-school [paper] calendar that you can just flip through. I usually have patients tick the days when they’re taking a medication, or the days when they’re debilitated by a migraine attack and they took medication.”

Solid communication between doctor and patient can also lead to patients using as-needed acute therapies for migraine in the early stages of an attack—something both Starling and Cooper advocate.

Along with these strategies are the therapeutic advances for migraine and headache disorders that have emerged since 2018, providing migraine specialists with novel tools and marking a new era in treatment. The agents mainly target CGRP, but new targets to explore have been identified as well.

“We know that in this country, about 1 in 1000 people have multiple sclerosis (MS). We also know that [the same number]— about 1 in 1000 people in the United States—are on a CGRP monoclonal antibody for prevention of headache. The same number of people with MS in the entire country are on the preventive CGRP monoclonal antibodies.” Cooper exclaimed. “It’s [very] rapid adoption.”

In addition to the therapies that focus on the CGRP inflammatory cascade or inflammation, lasmiditan (Reyvow), a therapy targeted to the 5-HT1F receptor, has been introduced. Lasmiditan’s benefits not only include the lack of blood vessel constriction, but having some targets located centrally in the nervous system, said Cooper.

Further, clinical trials, and often the primary end points required by the FDA, are experiencing a shift toward acute treatment. This includes explorations of some of patients’ most vexing symptoms, including photophobia, phonophobia, and nausea.

“I really appreciate that [these are now] end points in clinical trials because migraine is not just a headache. Migraine is not synonymous with ‘head pain.’ There are so many other disabling symptoms in migraine,” Starling said. Consequently, these end points have translated into real-world patient experience, she explained, in part because it is now expected that medications will address these issues.

“I think this is a good shift in the field of headache medicine, in the research world, the clinical world, and the patient advocacy world, that we should all be expecting more from our medications,” Starling said. And, “patients should be expecting more from not only their medications,” she concluded, “but from their headache treatment providers.”

neurologylive.com/perspectives-migraine-management

NeurologyLive Insights

A pair of migraine experts explores several topics in the acute treatment of migraine,
including recent therapeutic innovations.

Expert Perspectives on the Advances in the Management of Acute Migraine

was one of the few bright spots of 2020, with many pharmacologic options emerging for patients. Over the past 10 years, some therapies offered marginal improvements in efficacy and adverse effect profile compared with earlier generations of antiseizure medications (ASMs). The mold was broken in 2020 with a paradigm shift in what clinicians consider effective therapies, and agents that offer a significant improvement in quality of life.

In 2020, ASMs to treat focal seizure in adults, as well as seizures in Dravet syndrome, received FDA approval. Cenobamate (Xcopri) is a novel tetrazole alkyl carbamate derivative thought to work on both sodium and gamma-aminobutyric acid channels. In phase 2 study results, adults with focal epilepsy had median seizure reductions of 55.6%, 38.7% had a 75% or greater seizure reduction, and 28.3% were seizure-free in a post hoc analysis of the maintenance phase.

 In a dose-comparison study of cenobamate by Krauss and colleagues, median seizure reduction of 400 mg/D was 55%, and in the maintenance phase of the modified intent-to-treat cohort, the same dosing resulted in 65% seizure reduction.

 Although it is not possible to directly compare these rates of seizure freedom and reduction with pivotal trials of other ASMs, these rates are higher than those shown in the meta-analysis and pooled analysis of lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, zonisamide, pregabalin, lacosamide, eslicarbazepine, perampanel, and brivaracetam.

 If real-world experience is similar to the results of these pivotal trials, cenobamate may represent a new threshold for ASM efficacy in the treatment of focal epilepsy.

Similar paradigm changes may be afoot in the treatment of Dravet syndrome. In 2017, a North American consensus panel recommended valproic acid or clobazam as first-line therapies, with stiripentol, topiramate, or ketogenic diet as second-line treatments.

 Also in 2017, cannabidiol (Epidiolex) was FDA approved after demonstrating a median seizure frequency reduction of 43%.

 Fenfluramine (Fintepla), FDA approved in 2020 as well, demonstrated median seizure frequency reduction of 75% in its pivotal trial.

 As in the case of cenobamate, head-to-head comparisons of Dravet-specific therapies such as stiripentol, fenfluramine, and cannabidiol cannot be made. However, such impressive seizure reductions seen with both cenobamate and fenfluramine beg the question: Should we consider redefining what is considered a “significant” seizure reduction?

The abortive therapy space in epilepsy had languished with a paucity of therapies until 2019. The most recent FDA approval prior to then occurred in 1997 with rectal diazepam (Diastat), designed to allow caregivers to give an emergency-use medication to abort acute repetitive seizures. At the end of 2019, clinicians were given permission to prescribe FDA-approved nasal midazolam (Nayzilam) for patients 12 years and older. Its ease of use and clear dosing guidelines make it a valuable option for teenagers and adults. In 2020, nasal diazepam (Valtoco) also became available to US prescribers for patients 6 years and older; its advantages include dosing flexibility and long shelf life. Both of these nasal therapies met a previously unmet need for children and adults with epilepsy: an agent that can be quickly administered with greater social acceptability.

The focuses of epilepsy studies currently underway range from tantalizing first-in-class medications, new uses of older therapies, and even gene therapy, giving hope for more exciting developments in the coming year, even as we can reflect on the advances that emerged in 2020 in both prophylactic and abortive treatments for epilepsy.

REFERENCES
1. Chung SS, French JA, Kowalski J, et al. Randomized phase 2 study of adjunctive cenobamate in patients with uncontrolled focal seizures. 

. 2020;94(22):e2311-e2322. doi:10.1212/ WNL.0000000000009530
2. Krauss GL, Klein P, Brandt C, et al. Safety and efficacy of adjunctive cenobamate (YKP3089) in patients with uncontrolled focal seizures: a multicentre, double-blind, randomised, placebo-controlled, dose-response trial. 

. 2020;19(1):38-48. doi: 10.1016/S1474-4422(19)30399-0
3. Vossler DG. Remarkably high efficacy of cenobamate in adults with focal-onset seizures: a double-blind, randomized, placebo-controlled trial. 

, 2020;20(2):85-87. doi:10. 1177/1535759720903032
4. Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel. 

, 2017;68:18-34. doi:10. 1016/j.pediatrneurol.2017.01.025
5. Devinsky O, Cross JH, Laux L, et al; Cannabidiol in Dravet Syndrome Study Group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. 

. 2017;376(21):2011-2020. doi:10.1056/NEJMoa1611618
6. Lagae L, Sullivan J, Knupp K, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. 

. 2019;394(10216):2243-2254. doi:10. 1016/S0140-6736(19)32500-0

Letter From the Editor

Despite 2020 being a challenging year for those in medicine, the epilepsy therapeutic space featured a number of key steps forward.

2020 Epilepsy Review: Much to Be Excited About

About 2.8 million individuals worldwide, including 1 million in the United States, currently live with multiple sclerosis (MS), the leading cause of nontraumatic neurological disability.

 Investigators have been striving for decades to find more effective ways to diagnose and manage MS, but the “gold standard” of evidence-based care—use of randomized controlled trials—has not been as beneficial for this disease as it has for others. “MS is a condition that has a great degree of variability across people and across time,” said Aaron Boster, MD, president of the Boster Center for Multiple Sclerosis in Columbus, Ohio. As such, he explained to 

®, it can be difficult to draw evidence from the relatively small number of patients recruited for clinical trials and standard observational studies, as they do not accurately reflect the status of the disease in the real world.

Could big data provide a solution to this problem?

Big data refers, essentially, to a large volume of data that can either be structured or unstructured. In the medical context, these data are obtained from a variety of sources: medical records, hospital records, or data generated from wearable devices and health care apps. Over the past few years, efforts by players in the field have focused on creating repositories of information by establishing online registries for MS.

“Such volumes of information are not normally accessible to the average neurophysician, who, over the course of 20 to 30 years, usually ends up seeing only a couple of thousand patients with MS,” Boster said.

When analyzed statistically, big data can be used to spot patterns and generate evidence that is applicable to the entire MS population. “Big datasets essentially help us understand health. The greater the number of data points involved, the greater the learning,” explained Ava Battles, MPsychSc, chief executive officer of Multiple Sclerosis Ireland.

Multiple factors play a role in the severity of MS, a disease that is not completely understood. Its exact cause is poorly grasped as well, and boundaries remain extremely blurred between the 2 distinct disease forms: relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). These deficits, understandably, can hinder disease management.

MS registries can collect patient details and synthesize them into information that can help improve understanding of the disease process. For example, Boster cites the most accepted definition of SPMS, which was created by identifying 576 versions of the definition and comparing them with a cohort of patients from MSBase, an international database that contains information on patients with MS throughout the world.

 The definition that performed the best in terms of timely diagnosis, disease activity, and overall disease burden was selected from the data. Using the Expanded Disability Status Scale (EDSS), SPMS is defined by: a disability progression of 1 step in patients with EDSS 5.5 or less, and of 0.5 step in patients with EDSS 6 or higher in the absence of a relapse; a minimum EDSS score of 4; a pyramidal functional system (FS) score of 2; and confirmed progression over 3 months, including confirmation within the leading FS.

Big data may also help in the identification of various factors that can predict disease progression. “Currently, the standard for monitoring patients with MS is through clinical assessments and radiographic monitoring using MRI scans. This needs to be done yearly to look for the formation of new lesions,” Gauruv Bose, MD, clinical research fellow in MS at the Brigham Multiple Sclerosis Center in Boston, Massachusetts, explained to 

However, meeting this standard may not be feasible in locations where access to care is limited. MRI scans, in particular, can be expensive and are not always covered by insurance. Another use for these datasets is to identify cost-effective prognostic markers to help predict disease progression in different individuals. For instance, results of a longitudinal observational study published in 2020 explored risk factors for conversion of RRMS to SPMS by utilizing datasets from more than 15,000 patients.

 The investigators found that older age, a longer duration of illness, higher disability scores, and more relapses in the previous year could predict progression to SPMS. Conversely, other factors that were previously thought to be associated with progression, including oligoclonal bands in cerebrospinal fluid and evidence of spinal cord lesions, were found to not be associated with progression.

Another recent observational study attempted to identify early clinical markers for aggressive MS by collating data from MSBase datasets. After screening almost 10,000 patients whose data were recorded over 10 years, specific markers were pinpointed: older age at symptom onset and higher disability scores and occurrence of pyramidal signs during the first year of MS. Based on these data, clinicians encountering these features in a patient may choose to be more aggressive in their early intervention.

Patients with MS often suffer from other medical comorbidities, which may or may not influence MS progression, and big data helps comprehend the various effects of these comorbidities. For instance, an observational study identified that patients with psychiatric comorbidities such as mood or anxiety disorders were more likely to have increased neurological disability.

 Another recent cohort study retrieved data from MSBase and explored the association between pregnancy and clinically isolated syndrome (ie, the first episode of neurological symptoms in MS). Preliminary findings from this study suggest that pregnancy can forestall the onset of MS.

The detection increased risk of certain comorbidities in patients with MS may offer another role for these large datasets. A matched cohort study from 2 different databases showed that patients diagnosed with MS have a 2-fold increase in rates of venous thromboembolism and peripheral vascular disease when compared with patients without MS. Additionally, the incidence of myocardial infarction in female patients with MS was 2.5 times higher than in those without MS.

Increasingly, decision-making is a process shared between physician and patient. Patients cannot make informed treatment choices unless they are aware of the risks and prognosis of their condition. Particularly in young patients who are newly diagnosed with MS, the risks may not be immediately apparent. “There is a significant disease lag in MS,” Boster explained. “The brain damage that occurs in a 30-year-old does not cause clinical concern at that time because of neuroplasticity and a large neurological function reserve. Although there might be temporary loss of function, this is usually regained— but the brain damage is permanent. Over the years, increasing bouts of brain damage will eventually lead to accelerated volume loss and progression of disability.” Study results corroborate that MS risk knowledge can be relatively low among patients,

 confirming the importance of educating patients on self-care. Results gleaned from large datasets of patients with MS can be valuable in this endeavor.


There is a significant disease lag in MS. The brain damage that occurs in a 30-year-old does not cause clinical concern at that time because of neuroplasticity and a large neurological function reserve. Although there might be temporary loss of function, this is usually regained—but the brain damage is permanent.

One such tool that can be used to educate patients is the MS Severity Rank Calculator, developed by investigators at MSBase by plotting the EDSS scores of a consolidated large volume of patients over time. The calculator can be used to categorize individual patients into a specific decile. Patients can be shown where they rank on the graph, which is a powerful indicator of the severity of their disease status. “Showing patients their own natural history over the course of time is extremely valuable in terms of treatment adherence,” said Boster.

Randomized trial results may not always represent the real-world efficacy of a drug, but for MS agents, the differences may be even starker. Patients in randomized trials are usually treatment-naïve and therefore have less potential for interactions that could impact the efficacy of a drug.

 Assessment of the real-world efficacy of a given MS medication can be done on a much larger scale through big data than is possible with randomized trials. For example, research from registry datasets show that ocrelizumab is more associated with respiratory infections than are other drugs for MS— a finding that was not apparent in clinical trials.

“As opposed to almost no treatments 20 years ago, we now have 24 FDA-approved therapies to treat MS. But we still don’t know the best way of using them all,” said Boster. This situation is due in large part to the drugs’ diversity. “While some drugs have similar mechanisms of action, many have unique pharmacological properties, which in turn creates differences in efficacy, as well as different [adverse] effect risks, routes of administration, and monitoring requirements,” added Bose.

Consequently, patients aren’t always prescribed the medication that is best for them. “Not all countries allow patients to have the medication their neurologist recommends, without first ‘failing’ another choice, one that is often cheaper and relatively safer,” said Bose. “If clinicians could use evidence derived from big data to characterize and prognosticate their patients’ condition accurately, policymakers could be persuaded to [pay for] the right medication for higher-risk patients when it is first prescribed.”

All of these factors—correctly diagnosing and prognosticating the patient, educating patients about the importance of adhering to treatment, and choosing the right drug for treatment—contribute to making informed health care decisions. “With appropriate data, a clinician can take an individual’s physiology and lifestyle into account, and they can potentially provide a detailed, holistic treatment plan for a person living with MS,” said Battles.

Making informed treatment choices also includes timing treatments correctly. Although disease-modifying therapy is often only initiated after obvious neurological disability, such as walking issues, information from big data has shown that cognitive decline—a relatively less visible parameter—can often signal the beginning of MS.11 This is an emerging advance for care, in that it offers parameters to assess cognitive function earlier in the disease process.

While data is obtainable from various sources, the key sources of these datasets thus far for MS research have been disease registries. Unlike patient and hospital records, which capture data passively, disease registries actively encourage data entry and the sharing of information, and while relatively small, they have been growing. Several European MS registries have more than 500,000 total patients in their databases, potentially covering a large swath of the estimated 700,000 people with MS on the continent. As well, attempts have been made to harmonize the data between registries for additional insight, with the EUReMS and BMSD projects currently analyzing the results of this for datasets from over 60,000 and 100,000 patients, respectively.12 North America has been catching up slowly, and now several registries capture information from patients on this continent as well.

Four of the key big data sources for MS are as follows:

. An international registry, MSBase is open to neurophysicians worldwide. Patient data can be shared on this registry with appropriate consent, and these data can be used by investigators to track and evaluate outcomes. “The MSBase registry has capture visits from sites across many countries, and several excellent analyses have been done using this and similar datasets,” said Bose. MSBase currently has records from approximately 74,000 patients in 38 countries.

. Supported by the MS International Foundation, this database actively collects epidemiological information on MS worldwide. In addition to prevalence across various patient demographics, the database also offers information on health care resources’ availability and accessibility.

The North American Registry for Care and Research in MS

. This database links MS centers across the United States and Canada. A collaborative registry, it has repositories of clinical, genetic, and radiographic data of more than 800 patients with MS from 24 institutions.

. This new registry, whose name is an acronym for COVID-19 Infections in MS & Related Diseases, was formed in wake of the coronavirus disease 2019 (COVID-19) pandemic. It was established by the Consortium of Multiple Sclerosis Centers and the National Multiple Sclerosis Society to help investigate how COVID-19 affects the MS population, and it already contains data from about 900 patients with MS who have had COVID-19.

Challenges in Using Big Data for MS Research

The most common fear shared by both physicians and patients regarding these collections of information is breach of privacy. “Sharing your most private, most intimate information about your health has fear attached to it,” said Boster. “First is the fear that your data might fall into the wrong hands or be used inappropriately, and second, that datasets might actually limit your options for treatment.” Clinicians can mitigate patient fear by being open about how big data is used. Indeed, Battles stressed, “People consenting to their data being shared should be informed of who will have access to the data and what [they] will be used for. They should also know how to have their data removed, should they wish to do so at any time.”

Another key challenge is the inherent bias that these datasets may have. “There may be differences in the examination and rating tools used, although efforts are underway to standardize these,” said Bose. He added that incomplete or missing data can also create a bias. For instance, not all countries have the resources to allow frequent MRI examinations. Certain countries may not contribute to databases at all, creating a geographical bias. The Atlas of MS database records data from 138 countries, but it has excluded at least 80 countries where coordinators could not be identified. The world’s largest MS database, MSBase, has data from only 38 countries.

Despite these challenges, most patients are inclined to share their experiences and health data on global registries. “We see that patients are willing to fight back and do what it takes to contribute toward the understanding of the disease, whether this is participating in clinical trials or sharing their health information,” said Boster.

The Future of Big Data and Advances in MS

The wealth of insights that big data has the potential to offer is exciting, experts agree. According to Bose, one avenue of future research could be developing analytical tools that can be applied to big data to create and refine specific treatment algorithms. Another focus should be toward consolidating information across different databases, said Boster. “Increasing efforts at consolidating databases is essential so that we can have larger, robust, homogenous datasets to work from,” he noted.

Boster also expresses hope that consolidated big data can be applied to studying the prodromal stage of MS. “We know from the literature that for almost 5 years leading up to an MS diagnosis, patients have certain abnormal patterns, such as increased emergency [department] visits, pain, or psychiatric complaints. If we are ever to a priori identify the trappings of an MS prodrome, it is going to be through mining big data for clues and tips that lead us there,” he says. Identifying patients in the preclinical stages could certainly revolutionize the management of the disease, as the next logical step would be to identify treatment strategies that can stave off the clinical course altogether.

Multiple Sclerosis International Federation; 2020. Accessed January 9, 2021. https://www.msif.org/wp-content/uploads/2020/10/Atlas-3rd-Edition-Epidemiology-report-EN-updated-30-9-20.pdf
2. Lorscheider J, Buzzard K, Jokubaitis V, et al; MSBase Study Group. Defining secondary progressive multiple sclerosis. Brain. 2016;139(Pt 9):2395-2405. doi:10.1093/brain/aww173
3. Fambiatos A, Jokubaitis V, Horakova D, et al. Risk of secondary progressive multiple sclerosis: a longitudinal study. 

. 2020;26(1):79-90. doi:10.1177/1352458519868990
4. Malpas CB, Manouchehrinia A, Sharmin S, et al. Early clinical markers of aggressive multiple sclerosis. 

. 2020;143(5):1400-1413. doi:10.1093/brain/awaa081
5. McKay KA, Tremlett H, Fisk JD, et al; CIHR Team in the Epidemiology and Impact of Comorbidity on Multiple Sclerosis. Psychiatric comorbidity is associated with disability progression in multiple sclerosis. 

. 2018;90(15):e1316-e1323. doi:10.1212/WNL.0000000000005302
6. Nguyen A, Vodehnalova K, Kalincik T, et al. Association of pregnancy with the onset of clinically isolated syndrome. 

. Published online September 14, 2020. doi:10.1001/jamaneurol.2020.3324
7. Persson R, Lee S, Ulcickas Yood M, et al. Incident cardiovascular disease in patients diagnosed with multiple sclerosis: a multi-database study. 

. 2020;37:101423. doi:10.1016/j. msard.2019.101423
8. Giordano A, Liethmann K, Köpke S, et al; AutoMS Group. Risk knowledge of people with relapsing-remitting multiple sclerosis – results of an international survey. 

. 2018;13(11):e0208004. doi:10.1371/ journal.pone.0208004
9. Rojas JI, Pappolla A, Patrucco L, Cristiano E, Sánchez F. Do clinical trials for new disease modifying treatments include real world patients with multiple sclerosis? 

. Published online January 3, 2020. doi:10.1016/j.msard.2020.101931
10. Smoot KE, Stuchiner T, Lucas L, et al. Utilization, safety, and tolerability of ocrelizumab: year 2 data from the Providence Ocrelizumab Registry. Presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 11-13, 2019; Stockholm, Sweden. Accessed January 14, 2021. https://onlinelibrary.ectrims-congress.eu/ectrims/2019/ stockholm/278213/kyle.smoot.utilization.safety.and.tolerability.of.ocrelizumab.year.2.data.from. html?f=listing%3D3%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Asearch%3Docrelizumab
11. Cerqueira JJ, Compston DAS, Geraldes R, et al. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? J 

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12. Glaser A, Stahmann A, Meissner T, et al. Multiple sclerosis registries in Europe—an updated mapping survey. 

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Cover Story

Big data is on the precipice of revolutionizing multiple sclerosis knowledge and treatment.

How Big Data Can Drive Advancements in MS Research

 complex brain disorder that produces an assortment of neurological and systemic effects.

 Diagnosis is based on criteria related to the number and duration of attacks, as well as headache characteristics and the presence of accompanying symptoms.

 These symptoms are often debilitating and can be triggered by hormonal fluctuations or stress.

 Further, patients with migraine are more likely to experience medication overuse headache and comorbidities such as insomnia, depression, anxiety, gastric ulcers, and gastrointestinal bleeding.

Despite the prevalence and significant burden of migraine,

 the majority of patients living with the disorder are overlooked

 This is due in part to the challenge of identifying effective treatment to address the complex pathophysiology of migraine.

 Lack of efficacy and the development of adverse effects (AEs) often result consequently in patients’ dissatisfication with medications, particularly before the recent advent of more targeted preventive migraine treatments.

 The continued development of such agents promises to change this landscape.

Investigational migraine therapeutics focus on receptors of the trigeminovascular system, the activation and sensitization of which yields migraine headaches.

 Eptinezumab (Vyepti, Lundbeck Seattle BioPharmaceuticals), a humanized monoclonal antibody (mAb) inhibitor of the calcitonin gene-related peptide (CGRP), received FDA approval in February 2020 as the first intravenous migraine prophylactic in adults.6 Clinical trials,

 show that quarterly infusions of eptinezumab achieve 100% bioavailability

 after administration and significantly decrease the number of migraines experienced per month. Modulation of other signaling systems and factors which are involved upstream or alongside the trigeminovascular system (the endocannabinoid system

) are also being considered for therapy development. These factors can potentially be used in combination therapy with CGRP active agents.

 Of particular recent interest is the pituitary adenylate cyclase–activating peptide (PACAP) signaling pathway.

PACAP is a pleiotropic signaling neuropeptide

 belonging to the glucagon-growth hormone–releasing factor-secretin superfamily.

 It exists in 2 biologically active forms, PACAP-27 and PACAP-38.

 PACAP-38, the predominant form, shows a remarkable degree of evolutionary conservation.

 PACAP is known to regulate learning, memory, and behavior7,16 through its modulation of neuronal growth, development, and repair.

 It shares important close anatomical similarities with CGRP in central nervous system regions associated with migraine pathophysiology,

 suggesting that PACAP may play a role similar to that of CGRP in its contribution to migraine.

The PACAP pathway has shown promise as a potential novel therapeutic target in the treatment of migraine.

February 2021

Tapping Into the Potential of Cell and Gene Therapy

Parkinson Disease Treatment Tavapadon Aims to Benefit From Unique Multitrial Designs

Aducanumab and the Alzheimer Disease Treatment Landscape

Expert Perspectives on the Advances in the Management of Acute Migraine

2020 Epilepsy Review: Much to Be Excited About

How Big Data Can Drive Advancements in MS Research

PACAP Pathway and Its Role in Migraine

Sparing the Hippocampus in Epilepsy Surgery: Critical Decisions for Outcome Optimization

Sonja W. Scholz, MD, PhD, on Advancing Genomics Against Complex, Polygenic Neurodegenerative Disorders

Compounding Challenges: Conducting Clinical Trials in Alzheimer Disease